Creatine Safety, Tolerability, and Efficacy in Huntington's Disease: CREST-E Cellular energy depletion and secondary oxidative injury are present early, even presymptomatically in Huntington's disease (HD), and play a significant role in its pathogenesis. Creatine is an inexpensive and well-tolerated nutritional supplement that is converted in the body to phosphocreatine that acts as a high- energy phosphate store for restoring ATP from ADP. We have extensively shown creatine to delay the onset and slow the progression of the pathologic phenotypes in HD transgenic and knockin mice in a dose dependent manner and to correct their ATP deficiencies in brain. In our double-blind placebo-controlled study of 8 grams per day of creatine for 16 weeks in HD patients, we demonstrated that creatine is safe and tolerable, increases serum and brain levels of creatine, and markedly reduces a serum biomarker of oxidative injury to DNA (8OH2'dG) suggesting beneficial effects on a fundamental mechanism of pathogenesis in HD. We subsequently completed an open-label dose escalation study pushing creatine up to 40 grams daily. We found 30 grams daily to be the optimal dose based on serum and brain bioavailability, reduced tolerability at higher doses, dose dependent suppression of 8OH2'dG levels, evidence for slowed cognitive decline, and a sustained reduction in brain atrophy as determined by MRI morphometry. We now propose a multi-center, randomized, double-blind, placebo-controlled trial of 30 grams daily creatine in 650 symptomatic individuals with HD recruited from about 42 Huntington Study Group (HSG) sites, treated for 36 months to test the hypothesis that it will slow the progressive functional decline of HD. Our secondary clinical aims are to assess safety and tolerability by analyzing clinical and laboratory adverse events and to assess the clinical impact of creatine on impressions of global health (CGI), quality of life measures (SF-36), and on motor, cognitive, psychiatric, behavioral, and functional symptoms of HD. We also propose collaborating with a program project on HD biomarkers to provide additional secondary endpoints and to exploit this first opportunity to assess and validate particular biomarkers in a large prospective HD clinical trial. We have conceived a design incorporating interim analyses of safety, futility, and efficacy that would provide early and repeated safety data and also permit early stopping or modification. A companion application is also submitted to support study coordination, data management, and biostatistical support under the auspices of the HSG (Bernard Ravina, principal investigator).